This invention relates to polymeric compounds which have been demonstrated in rats and mice to have utility in the immunoregulatory management of tumor therapy.
Although the field of tumor therapy has been the subject of extensive study, very few effective compounds for such use have been found so far.
According to one approach, attempts are made to manipulate the body's immune system. For example, it is generally recognized that the thymus gland is of great importance in the development and senescence of immunological competence. By various mechanisms believed to be principally hormonal, the thymus gland exerts control over the T-lymphocyte mediated immune function. A variety of naturally-occurring and synthetically prepared peptides have thus been tested as stimulants and/or suppresants of this immune system with varying results.
Other agents that have been found to have immune adjuvant activity include, for example, Bacillus Calmette-Guerin (BCG), Corynebacterium parvum, glucan, levamisole and tilorone. Some of these compounds increase the production of antibodies while others either enhance or inhibit cell-mediated immunity.
Various biologically active synthetic polyelectrolytes also have been proposed as useful antitumor agents. Thus, Regelson and Holland found a wide spectrum of antitumor activity in mice for the sodium salt of polyethylenesulfonate. Nature (London) 181, 46 (1958). A number of carboxylic acid polymers of substantially high molecular weight, for example, polyacrylic acid, polymethacrylic acid, and ethylenemaleic anhydride copolymer (EMA) were then found to have antineoplastic activity similar to that of sodium polyethylenesulfonate. Regelson et al., Nature (London) 186, 778-80 (1960); Regelson, "Water-Soluble Polymers", in "Polymer Science and Technology", Vol. 2 (ed. N. K. Bikales), pp. 161-77, Plenum Press, New York, 1973. The antineoplastic activity of the EMA type polymers also is disclosed in Canadian Pat. No. 664,326, corresponding to U.S. Application Ser. No. 758,023, filed Oct. 28, 1958, now abandoned. The useful molecular weight of these polymers is said to range between 500 and 1.5 million. One of these polymers, the half-amide, half-ammonium salt of EMA having an average molecular weight of 20,000-30,000, was later reported to be chronically toxic in rodents and dogs. Mihich et al., Fed. Proceedings, Vol. 19, No. 1, Pt. 1, March 1960. Chronic toxicity also was later reported with the 2000-3000 molecular weight polymer in dogs by Mihich et al. Fed. Proceedings, Vol. 20, No. 1, Pt. 1, March 1961. These findings of toxicity militated against clinical testing of the polymers.
Subsequently, the related 1:2 divinyl ether-maleic anhydride copolymer showed antitumor activity in tests conducted by the National Cancer Institute. Breslow, Pure & Appl. Chem. 46, 103-13 (1976). This copolymer also is known as pyran copolymer or DIVEMA, and one well-known sample has been designated NSC 46015. The use of these pyran copolymers as anti-tumor agents also is disclosed in U.S. Pat. Nos. 3,224,943 and 3,794,622, wherein the useful molecular weight is described as ranging from 5000-30,000. The antitumor activity of pyran copolymer has been attributed to an immunopotentiation or to an effect upon the immune response through the recticuloendothelial system (RES) by enhancing macrophage function in a number of papers which include, for example, Breslow, Pure & Appl. Chem. 46, 103-13 (1976); Mohr et al., Prog. Cancer Res. Ther. 7, 415-26 (1978); Schultz et al., id. 7, 459-67 (1978); and Dean et al, Cancer Treatment Reports 62, September 1978.